session introduction · go? reatment of breast cancer has undergone quite an improvisation in the...

10.30am -11.00 am - Registration

12.15 pm - 12.45 pm - Coffee Break

12.45 pm -01.15 pm --- Oral Presentation by Chenbo Zeng Topic :-Sigma-2 receptor ligand as a novel method for delivering a SMAC mimetic drug for treating ovarian cancer

01.15 pm - 02.15 pm --- Lunch Break

02.15 pm - 02.45 pm --- Oral Presentation by Elise Verron Topic :-Innovative nanoformulation of curcumin to prevent breast cancer bone metastasis

02.45 pm - 03.15 pm --- Oral Presentation by David Vesely Topic :-Cardiac Hormones for the treatment of Cancer

03.15 pm - 03.45 pm --- Oral Presentation by Claudio Pusceddu Topic :-Percutaneous Cryoablation in the treatment of lung cancer

03.45 pm - 04.00 pm --- Coffee Break

--- Day 1 End ---

Day 1 : January 23rd 2017

11.00 am -11.15 am - Inaugural session

11.15 am -11.30 am - Group photo

Keynote Forum

11.30 am -12.15 pm - Krishna Murthy

Kidwai Memorial Institute of Oncology, Bangalore, India

Session Introduction

WSCST 2017

11.00 am -11.30 am --- Oral Presentation by Jixin Dong Topic :-The Hippo-YAP Pathway in Prostate Cancer

11.30 am -12.00 pm --- Oral Presentation by Howard Yang Topic :- Reproducible genes for breast cancer patient survival prediction

12.00 pm- 12.30 pm --- Coffee Break

12.30 pm -01.00 pm --- Oral Presentation by Maurizio Memo Topic :-Tropomodulins are new favorable prognostic biomarkers in high-risk Neuroblastoma

01.00 pm -02.00 pm --- Lunch Break

02.00 pm-02.30 pm --- Oral Presentation by Run-Sheng Ruan Topic :-Clinical and immunological response to in vivo whole cancer cell antigen priming followed by adoptive T-cell therapy in terminal cancers

02.30 pm - 03.00 pm --- Oral Presentation by Elise Verron Topic :- Gallium as a promising candidate for the treatment ofpatients with bone

03.00 pm -03.30 pm --- Poster Presentation by Suhn-Young Im Topic :-Mechanism of CK2a activation and its expression in human breast cancer

03.30 pm -04.00 pm --- Poster Presentation by Seonghui Jang Topic :-Heterogeneous ribonucleoprotein E1 and E2 regulate BC200 RNA-mediated translation inhibition

04.00 pm -04.15 pm --- Coffee Break

--- Day 2 End ---

Day 2 : January 24th 2017

WSCST 2017

www.bioleagues.com

ISBN: 978-81-932966-1-5 January 23 - 25, 2017

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23rd – 25th January 2017, Singapore

Dr S Krishnamurthy Dr S Krishnamurthy

Professor & HOD of Surgical Oncology

Kidwai Memorial Institute of Oncology.

Breast Cancer in India- Where do we stand and where do we

go?

reatment of Breast cancer has undergone quite an improvisation in the last

20 years since the introduction of molecular biology, immunohistochemistry

and availability of targeted therapy.We present our last 6 years’ experience in

treating 862 Breast cancer patients in a single unit at a Regional cancer centre

in India. Total of 862 breast cancer patients have been treated at our institute in

a singlesurgical oncology unit from 2010 to 2016. Maximum incidence was

observed in the age group 35-64 years (710/82.4%) and least in above 65 years

(73/ 8.5%) with almost an equal number of patients coming from rural (51.9%)

and urban (48.1%) population. Right sided breast cancer (56%) dominated

compared to left (43.4) whereas 0.6% were bilateral. A higher incidence was

noted amongst postmenopausal (54.2%) compared to premenopausal women

(45.8%). Maximum patients were of Luminal A category (35%) with most of them

presenting as Stage II (42.5%) and III (44.4%) disease. Triple Negative tumours

contributed to significant 32.7% of the disease. 338 patients were given

neoadjuvant chemotherapy before surgical management. 21 patients underwent

Breast conservation surgery with Sentinel Lymph node biopsy done in 9 patients

with 100% sentinel Lymph node identification rate while the rest underwent

modified radical mastectomy. Adjuvant chemotherapy and Radiotherapy was

T

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administered to 437 and 702 patients respectively whereas 198 patients were

given targeted therapy. Hormonal therapy was offered to 460 patients based

upon their receptor status.In a developing country where health insurance cover

and governmental policy is not available for the patients, it remains a challenge

to offer the advanced management to all patients attending a regional cancer

centre.

Biography

M.ch SURGICAL ONCOLOGY (AUGUST 1994); M.S.GENERAL

SURGERY (FEBRUARY 1987); M.B.B.S (JULY 1982). Joined the

institute as lecturer in 1987, promoted as assistant professor 1993,

professor 2002 and heading the department of surgical oncology since

2015. Teaching super specialty students (8) every year, published 40

articles in national/ international journals, participated in 8 global

projects.

CONTENTS

SL.NO TITLES AND AUTHORS PAGE NO

1. Sigma-2 Receptor Ligand as a Novel Method for Delivering a

SMAC Mimetic Drug for Treating Ovarian Cancer 1

Chenbo Zeng

2. Percutaneous Cryoablation in the Treatment of Lung Cancer 2

Pusceddu Claudio

3. NMK-BH2, A Novel Microtubule Disrupting Agent, Induces Apoptosis

And Autophagy In Cervical Cancer Cells By Binding To Tubulin 3 – 4

Dipanwita Mukherjee

N. Maruthi Kumar

Dalip Kumar

Gopal Chakrabarti

4. Gallium as a Promising Candidate for the Treatment of Patients with Bone

Metastasesfrom Breast Cancer 5 – 6

StrazicI

Schmid-Antomarchi H

Schmid-Alliana A

Bouler JM

ScimecaJC

Verron E

5. On Consolidated Predictive Model of the Natural History of Breast Cancer Considering

Primary Tumor and Secondary Distant Metastases Growth 7 – 8

Ella Y. Tyuryumina

Alexey A. Neznanov

6. Reproducible Genes For Breast Cancer Patient Survival Prediction 9

Howard Hua Yang

7. Biology of Cell-Free Nucleic Acids and Its Role in Initiation And Metastasis of Cancer 10

Professor Indraneel Mittra

8. Combining this 6-miRs panel with clinicopathologic factorsor the Detection of

Early Relapse in Postoperative Colorectal Cancer Patients 11

Jaw Yuan Wang

9. The Hippo-YAP Pathway in Prostate Cancer 12

Jixin Dong

CONTENTS


10. Tropomodulins are new Favorable Prognostic Biomarkers in

High-Risk Neuroblastoma 13 – 14

Paola Bettinsoli

Giulia Ferrari-Toninelli

Sara Anna Bonini

Michela Guarienti

Davide Cangelosi

Luigi Varesio

Maurizio Memo

11. High-Dose Intravenous Vitamin C as Sole Therapy and in Combination with

Cytotoxic Chemotherapy in Patients with Cancer 15

Nina Mikirova

12. Clinical And Immunological Response to in Vivo Whole Cancer Cell Antigen

Priming Followed By Adoptive T-Cell Therapy in Terminal Cancers 16

Runsheng RUAN

13. Mechanism of CK2 Activation and its Expression in Human Breast Cancer 17

Shun Young Im

14. Cardiac Hormones for the Treatment of Cancer 18

David Vesely

15. The Combination of Zingiberis officinale var.rubrum and Piper retrofractum Based on

Microencapsulation Technology as an Anticancer Drug 19

Doni Dermawan

16. New Topoisomerase Inihibitor for Breast and Pancreas Cancer 20 – 21

Palma Giuseppe

Mariconda Annaluisa

Rea Domenica

Barbieri Antonio

Domenico Iacopetta

Maria Stefania Sinicropi

Longo Pasquale

Arra Claudio

Saturnino Carmela

17. Distinct Functional Roles of Cancerous Immunoglobulins in Cancer Immunology 22

Gregory Lee

18. Prevalence, Risk Factors and Disease Knowledge of Breast Cancer in Pakistan 23

Hafiz Muhammad Asif

CONTENTS


19. Tillandsia recurvata: A Natural Plant with Anti-Prostate Cancer

Potential Targeting Kinases 24

Henry I.C. Lowe

20. Nutrition Therapy For Breast Cancer During Chemotherapy A Qualitative Study onthe

Needs of Breast Cancer Patients 25

Laili Rahayuwati

Witdiawati

Erna Irawan

21. Prognostic Value of Breast Cancer Subtypes Based on ER/PR, Her2 Expression

and ki-67 Index in Women Received Adjuvant Therapy after Conservative Surgery

for Early Stages Breast Cancer 26 – 27

Menna Fouda

Fawzy Z. Sherif

Amr A.Ghannam

Safinaz H. Al-shorbagy

Menna Fouda

22. Functional Foods in the Primary Prevention of Colon Cancer 28

Mostafa I. Waly

23. Association Between Environmental Tobacco Smoke Exposure and Lung

Cancer Susceptibility: Modification by Antioxidant Enzyme Genetic Polymorphisms 29

Muna Fathy

24. VEGF and IL-6 Profile in Patients with Invasive Breast Cancer 30 – 31

Srabović N

Softić A

Smajlović A

Mujagić Z

25. DNA methylation Analysis of genes in Notch signalling pathway in human

glioblastoma FFPE tissues 32

Rajeswari Narayanappa

Madhuri Aithal

26. Exosomal Formulation Enhances Therapeutic Response of Celastrol

Against Lung Cancer 33 – 34

Farrukh Aqil

Radha Munagala

Hina Kausar

Ashish Agrawal

Jeyaprakash Jeyabalan

Al-Hassan Kyakulaga

Ramesh Gupta

CONTENTS


28. Regulatory T Cells; Key Role Players in Hematological Malignancies 35

Dr. Rania Zayed

29. Prevalence of Epstein–Barr Virus Genotypes in Pakistani Lymphoma Patients 36 – 37

Sadia Salahuddin

Joharia Azhar

Christopher B. Whitehurst

Ishtiaq Qadri

Julia Shackelford

Joseph S. Pagano

Kristy L. Richards

30. Design, Synthesis and Evaluation of Novel Pyridazine Pharmacophores on

Migration and Invasion, A Major Event of Cancer Metastasis 38

Yasser Hussein Eissa Mohammed

Prabhakar B.T

Shaukath Ara Khanum

31. An Ounce of Prevention is Worth a Pound of Cure"-Gnrh-Acotreatment Significantly

Preserves Fertility and Increases Pregnancy Rate in Addition to Cyclic Ovarian Function 39

Zeev Blumenfeld

32. Quinacrine Induces Apoptosis in Cancer Cells by Forming a Functional Bridge

Between TRAIL-DR5 Complex and Modulating the Mitochondrial Intrinsic Cascade 40 – 41

Chanakya Nath Kundu

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Chenbo Zeng University/Organization: University of Pennsylvania Perelman School of Medicine

Sigma-2 Receptor Ligand as a Novel Method for Delivering a SMAC Mimetic Drug for Treating Ovarian Cancer

e have developed a new strategy to deliver anticancer drugs selectively into tumor cells by

targeting sigma-2 receptors. Sigma-2 receptors are overexpressed in various tumor cells. The

radiolabeledsigma-2 receptor ligand, [18F]ISO-1,provided high contrast images of solid tumors in

cancer patients by the Positron Emission Tomography (PET). Sigma-2 ligands are rapidly internalized

into cancer cells by endocytotic pathways and localize in multiple subcellular organelles such as

lysosomes, mitochondria and the endoplasmic reticulum. These data suggest that sigma-2 receptor

ligandsare an excellent candidate for delivering anticancer drugs selectively to tumors. We conjugated

a sigma-2 ligand, SW43, to a second mitochondria-derived activator of caspase (SMAC) mimetic drug.

The resulting compound, SW III-123, successfully delivered the SMAC mimetic to ovarian cancer cells,

suppressed tumor growth and improved mouse survival. Mechanistically, SW III-123 induced rapid

degradation of inhibitor of apoptosis proteins (cIAP1 and cIAP2), accumulation of NF-κB-inducing

kinase (NIK) and activation of caspase-8, -9 and -3. Tumor necrosis factor alpha (TNFα) antibody

markedly blocked SW III-123-induced cell death and caspase-3 activity. The data suggest that SW III-

123 activated NF-κBand apoptotic pathways. In conclusion, sigma-2 ligands are a promising tumor-

targeting drug delivery agent. Sigma-2-conjugated SMC exemplifies a novel class of cancer

chemotherapeutics.

Biography Dr. Zeng obtained her Ph.D. in biochemistry at Iowa State University inthe United States. Since then she

worked at Washington University School of Medicineas a postdoc and then as a research instructor until 2013.

Currently she is a Research Assistant Professor at the Department of Radiology, University of Pennsylvania,

PerelmanSchool of Medicine. Her research has been focusing on development of chemotherapeutic drugs by

targeting the sigma-2 receptor.

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Pusceddu Claudio University/Organization: Oncology Hospital – AOB Cagliari - Italy

Percutaneous Cryoablation in the Treatment of Lung Cancer

ung cancer is the most commonly diagnosed cancer in the United States and Europe and it is a

major cause of cancer death. Surgical resection, when possible, offers the best chance of healing of

NSCLC in selected patients and in early stage. In patients not candidates for surgery, chemotherapy

and radiotherapy are mainly palliative. Cryoablation is a minimally invasive technique, highly

innovative, which has only recently been used in the treatment of primary and secondary lung tumors.

Cell death is obtained as a result of rapid freezing followed by slow thawing that causes necrosis of the

target tissue. Cryoablation can be proposed with radical intent (curative) in cases of disease limited to

the lung; individual tumors no larger than 5 cm or up to 5 multiple tumors confined to no larger than 3

cm each one. The advantages of cryoablation are due to very precise control of the treated area (display

of the iceball) sparing the surrounding healthy tissues. The major risks and complications of

pulmonary cryoablation are those deriving from interventional treatment such as: local hematomas,

pneumothorax, pulmonary bleeding caused by wrong placement of the cryoprobes and infections.

Biography Dr. Pusceddu Claudio graduated in March 1986 from the University of Cagliari (Italy) and specialized at the

same university in Diagnostic Radiology in 1996 and in Medical Oncology in 2004. He has worked in an

oncological hospital since 1992, and he has specialized in extra-vascular interventional radiology in the field of

oncological disease. Every year he performs more than three hundred procedures (Radiofrequency thermal

ablation, Microwave ablation, Cryoablation, Percutaneous screws fixation, Osteoplasty with PMMA injection and

combination of these procedures) in cancer patients.

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Dipanwita Mukherjee Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of

Calcutta, Kolkata-700019, West Bengal, India

N. Maruthi Kumar Department of Chemistry, Birla Institute of Technology and Science, Pilani- 333031, Rajasthan, India.

Dalip Kumar Department of Chemistry, Birla Institute of Technology and Science, Pilani- 333031, Rajasthan, India.

Gopal Chakrabarti Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of

Calcutta, Kolkata-700019, West Bengal, India

NMK-BH2, A Novel Microtubule Disrupting Agent, Induces

Apoptosis And Autophagy In Cervical Cancer Cells By Binding To Tubulin.

ervical cancer remains one of the most common causes of cancer-related death among women in

developing countries. Microtubules, being a validated anti-cancer drug target, prompted innovation

of novel anti-mitotic chemotherapeutics which could overcome systemic toxicity related limitation of

the clinically used anti-cancer drugs.

This study aims to explore the detailed anti-cancer mechanism of NMK-BH2, a novel bis-

indolyl-hydrazide-hydrazone derivative based on indole scaffold. According to our data, the anti-

proliferative activity of NMK-BH2 was selective towards cervical cancer (HeLa) cells compared to

normal cells, thus conferring therapeutic advantage of reduced host toxicity. NMK-BH2 caused G2/M

arrest followed by mitochondria-mediated apoptosis through depolymerisation of cellular interphase

and spindle microtubules. It also induced lethal autophagy, independent of apoptosis, contributing to

enhanced cytotoxicity in HeLa cells. Characterisation of NMK-BH2 –tubulin interaction in cell-free

system revealed that NMK-BH2 inhibited the microtubule assembly through strong and specific

binding to tubulin at a single site, overlapping with colchicine-binding site on tubulin.

C

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In conclusion, the present study suggests NMK-BH2 as an efficient and selective anti-cancer agent

endowed with remarkable ability to target the cellular microtubule system, leading to apoptosis and

autophagy-mediated cell death in HeLa cells and thus, inspires its establishment as a promising

candidate for cervical cancer chemotherapy.

Biography I, Dipanwita Mukherjee, have been working as Senior Research Fellow (CSIR) at Department of Biotechnology,

University of Calcutta (India). I have obtained M.Sc. in Biotechnology (Jadavpur University, India) and received

Junior Research Fellowship award from Council of Scientific and Industrial Research (CSIR). I have participated

in national and international conferences and seminars for oral and poster presentations and published my

research findings in peer-reviewed international journals. My research interest is development of novel

chemotherapeutics as potential anti-cancer agents by targeting tubulin-microtubule system and understanding

the involvement of autophagy in modulating the therapeutic efficacy of these anti-cancer agents.

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StrazicI Université Côte d’Azur, CNRS, INSERM, iBV, France, GRAFTYS SA, 13854 Aix en Provence, cedex 3, France

INSERM, U791, LIOAD, Nantes, F-44042, France

Schmid-Antomarchi H Université Côte d’Azur, CNRS, INSERM, iBV, France.

Schmid-Alliana A Université Côte d’Azur, CNRS, INSERM, iBV, France

Bouler JM Université Nantes, CNRS, Nantes, France

ScimecaJC Université Côte d’Azur, CNRS, INSERM, iBV, France

Verron E INSERM, U791, LIOAD, Nantes, F-44042, France

Gallium as a Promising Candidate for the Treatment of

Patients with Bone Metastasesfrom Breast Cancer

one metastases of breast cancer typically lead to a severe osteolysis resulting from unbalanced

bone metabolism. On the other hand, the semi-metallic element gallium (Ga)is an inhibitor of bone

resorption. Thus, using an establishedin vitro model associating conditioned medium from breast

cancer cells withosteoclast precursor cells, we exploredGa activity on osteoclastogenesis in an

aggressive bone metastatic environment. We first observed that Ga dose-dependently inhibited

osteoclastogenesis induced by tumour cells medium. To mimic a more aggressive environment where

pro-tumorigenic factors are released from bone matrix, metastatic breast tumour cells were stimulated

with TGF-, a major cytokine involved in bone metastasesdevelopment. In these circumstances, Ga

still inhibited cancer cells medium-driven osteoclastogenesis. Lastly, we evidenced that Ga directly and

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strongly impacted cancer cellsproliferation/viability, as well as the expression of major osteolytic

factors.

This is the first time that antitumor properties of Ga have been specifically studied in the

context of bone metastases. Our data strongly suggest that, through its action against the vicious cycle

involving bone cells and tumour cells, Ga represents a relevant and promising candidate for a local

deliveryupon the resection of bone metastases from breast cancer.

Biography After getting her PharmD, she has completed her PhD in 2009 from INSERM-U791 (laboratory of osteo-articular

engineering-Nantes University-France) and postdoctoral studies from Nice University School of Medicine (CNRS

genetic and physiopathology of bone disorders). She accomplished her academicals mobility in the

nanoformulation of anticancer drugs in the University of Sydney(Australia). Her research career is focused on

regenerative medicine for bone tissue especially by designing innovative drug-combined systems and evaluating

their efficacy and safety. She is lecturer at the pharmaceutical sciences faculty. She has published more than 25

research articles in international reputed journals, 4 chapters of book and has been serving as reviewer of

scientific journals.

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Ella Y. Tyuryumina International Laboratory for Intelligent Systems and Structural Analysis (ISSA), National Research University Higher

School of Economics, Russia

Alexey A. Neznanov International Laboratory for Intelligent Systems and Structural Analysis (ISSA), National Research University Higher

School of Economics, Russia

On Consolidated Predictive Model of the Natural History of Breast Cancer Considering Primary Tumor and Secondary

Distant Metastases Growth

his study is an attempt to obtain reliable data on the natural history of breast cancer growth. We

analyze the opportunities for using classical mathematical models (exponential and logistic tumor

growth models, Gompertz and von Bertalanffy tumor growth models) to try to describe growth of the

primary tumor and the secondary distant metastases of human breast cancer. The research aim is to

improve predicting accuracy of breast cancer progression using an original mathematical model

referred to CoMPaS and corresponding software. We are interested in: 1) modelling the whole natural

history of the primary tumor and the secondary distant metastases; 2) developing adequate and precise

CoMPaS which reflects relations between the primary tumor and the secondary distant metastases; 3)

analyzing the CoMPaS scope of application; 4) implementing the model as a software tool.

The CoMPaS is based on exponential tumor growth model and consists of a system of

determinate nonlinear and linear equations; corresponds to TNM classification. It allows to calculate

different growth periods of the primary tumor and the secondary distant metastases: 1) "non-visible

period" for the primary tumor; 2) "non-visible period" for the secondary distant metastases; 3) "visible

period" for the secondary distant metastases. The CoMPaS is validated on clinical data of 10-years and

15-years survival depending on the tumor stage and diameter of the primary tumor (1. Engel J. et al.

Eur J. Cancer. 2003; 39(12): 1794-1806; 2. Engel J. et al. Int. J. Radiat. Oncol. Biol. Phys. 2003; 55(5):

1186-1195; 3. Engel J. et al. Cancer Metastasis. 2012; 31(1-2): 235-246). The new predictive tool: 1) is a

solid foundation to develop future studies of breast cancer growth models; 2) does not require any

expensive diagnostic tests; 3) is the first predictor which makes forecast using only current patient

data, the others are based on the additional statistical data.

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The CoMPaS model and predictive software: a) fit to clinical trials data; b) detect different

growth periods of the primary tumor and the secondary distant metastases; c) make forecast of the

period of the secondary distant metastases appearance; d) have higher average prediction accuracy

than the other tools; e) can improve forecasts on survival of breast cancer and facilitate optimization of

diagnostic tests.

The following are calculated by CoMPaS: the number of doublings for «non-visible» and «visible»

growth period of the secondary distant metastases; tumor volume doubling time (days) for «non-visible»

and «visible» growth period of the secondary distant metastases.

The CoMPaS enables, for the first time, to predict "whole natural history" of the primary tumor

and the secondary distant metastases growth on each stage (pT1, pT2, pT3, pT4) relying only on the

primary tumor sizes. Summarizing: a) CoMPaS describes correctly the primary tumor growth of IA,

IIA, IIB, IIIB (T1-4N0M0) stages without metastases in lymph nodes (N0); b) facilitates the

understanding of the appearance period and inception of the secondary distant metastases.

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Howard Hua Yang University/Organization: National Cancer Institute at NIH, USA

Reproducible Genes For Breast Cancer Patient Survival Prediction

e have analyzed the dataset METABRIC to find reproducible genes to form linear and nonlinear

models for survival prediction. We drew random half samples from the training data as bootstrap

samples and applied the Cox Proportional Hazards Model to analyze the full training data and each

half sample with the adjustment for the four clinical variables: age, ER, tumor size, and node. From

the analysis of the full training data, we selected top 330 genes (top 1%). We selected 50 genes most

reproducible in the analyses of the bootstrap samples with repetition rate greater than 0.36. The 50

selected genes include TFRC (one of 21 Oncotype DX genes) and other cancer genes such as PAWR,

PKM2, STAT5Band ANGPT2. We used linear/nonlinear predictors to combine the expression of the

selected genes. We used the validation data to examine the generalization performance of the

predictors with adjustment for age, ER, tumor size, and node. The nonlinear model gave a signature

with HR=1.7, CI:1.39-2.08 and P= 2.552e-07 better than the linear model. The METABRIC data

analysis showed that the patients with high expression of STAT5Bhad better prognosis while those

with high expression of TFRC had poor prognosis. The analysis of the tamoxifen treatment data

showed that TFRC expression can be reduced by taking Tamoxifen without changing STAT5B. Our

further understanding about these genes has clinical implications in breast cancer treatment.

Biography:

Dr. Yang received his PhD inProbability and Statistics in 1989 from Zhongshan (Sun Yat-Sen)

University, China. Before he joined the NCI as an expert/staff scientist in 2001, he was a productive

scientist in signal processing, neural networks and machine learning. Since 2001, he had been focused

on biostatistics and bioinformatics in cancer research.

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Prof. Indraneel Mittra University/Organization: Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer

(ACTREC), Mumbai. India

Biology of Cell-Free Nucleic Acids and Its Role in Initiation

And Metastasis of Cancer

everal hundred billion to a trillion cells die in the adult human body daily, and a considerable

amount of fragmented cell-free nucleic acids (cfNAs) from dying cells are released into the

circulation. Our research has shown that circulating cfNAs can freely enter into healthy cells,

accumulate in their nuclei, trigger a DNA damage repair response (DDR) and integrate into host cell

genomes by an unique mechanism (http://www.ias.ac.in/article/fulltext/jbsc/040/01/0091-0111;

http://f1000research.com/articles/4-924/v1). Similarly, at the tissue level, locally generated cfNAs from

dead cells can be taken-up by healthy bystander cells to induce DDR that facilitates their integration

into recipient cell genomes. Genomic integration of cfNAs leads to dsDNA breaks, inflammation,

chromosomal instability, senescence and apoptosis of recipient cells. cfNAs from cancerous cells can

cause oncogenic transformation of NIH3T3 cells which are tumourigenic in immune-deficient mice.

These findings raise a new hypothesis of cancer metastasis which posits that metastasis arises from de

novo oncogenic transformation of cells of target organs induced by cfNAs arising from apoptotic

circulating tumour cells (CTCs). This hypothesis challenges the current dogma that metastasis are

produced by growth of CTCs that are lodged in distant organs.

Biography: Professor Mittra obtained his medical degree from University of Delhi and is a Fellow of the Royal College of

Surgeons of England and holds a PhD degree from University of London. He did his post-doctoral training with

Dr Renato Dulbecco, Nobel Laureate, at the Imperial Cancer Research Laboratories in London. Professor Mittra

is a multi-faceted personality. He is a breast cancer surgeon while at the same time being deeply involved in

public health and basic research in cancer. Professor Mittra’s current research interests lie in the area of biology

of extracellular nucleic acids and their role in ageing, inflammation, degenerative disorders and initiation and

metastatis of cancer.

S

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Jaw Yuan Wang MD, Ph.D Kaohsiung Medical University Hospital,Kaohsiung Medical University,

Kaohsiung 807, Taiwan

Combining this 6-miRs panel with clinicopathologic factorsor

the Detection of Early Relapse in Postoperative Colorectal Cancer Patients

icroRNA (miR) deregulation is associated with colorectal cancer (CRC) development and

recurrence; therefore, miRs may be reliable biomarkers for detecting early relapse

postoperatively. Ten candidates were identified using miR arrays: miR-7, miR-31, miR-93, miR-141,

miR-195, miR-375, miR-429, miR-494, miR-650, and let-7b. Substantial differences were observed in

their expression levels between early relapsed and non-early relapsed CRC patients. Using a miR RT-

qPCR, we observed that expression levels of miR-93, miR-195, and let-7b were significantly decreased,

whereas those of miR-7, miR-141 and miR-494 showed increases that were more significant in the CRC

tissue samples from the early relapsed patients than the non-early relapsed patients. A panel of 6 miRs

(miR-7, miR-93, miR-195, miR-141, miR-494, and let-7b), at a cut-off value of 2 deregulated miRs,

distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 76.6% and a

specificity of 71.4%. By combining this 6-miRs panel with 6 clinicopathologic factors, at a cut-off value

of 4, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 89.4% and a

specificity of 88.9%.This study showed that the developed miR panel has the potential to improve

predicting early relapse in CRC patients.

Biography: Prof. Jaw-Yuan Wang is Vice superintendent at Kaohsiung Medical University Hospital (KMUH). He went on to

receive further training as a Research Fellow at the State University of New York, Stony Brook, USA. He now

serves as Leader of Colorectal Cancer Multidisciplinary Team, Program Director of Robotic Surgery. He is an

active member in numerous professional organizations. Besides being a recipient of numerous awards, he has

published widely at least 245 peer-reviewed papers and 4 book chapters. He is a reviewer for more than 40

prestigious journals and is now the PI of Biosignature in Colorectal Cancers, Academia Sinica, Taiwan.

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Jixin Dong, Ph.D Fred& Pamela Buffett Cancer Center and Eppley Cancer Institute, University of Nebraska Medical Center, Omaha,

NE68198, USA.

The Hippo-YAP Pathway in Prostate Cancer

rostate cancer is the most common malignancy and the second leading cause of cancer-related

mortality among men in the United States. Although androgen-deprivation therapy (medical or

surgical castration) is highly effective for advanced prostate cancer, the majority of patients eventually

develop resistance and progress to castration-resistant prostate cancer (CRPC). Unfortunately, most

cases of CRPC are currently incurable. The cause of castration resistance is still not completely known.

Recent genetic mouse models and studies with cancer patients firmly demonstrated the critical roles of

Hippo signaling in cancer development. Yes-associated protein, YAP, is an effector of the Hippo tumor

suppressor pathway. The oncoprotein YAP has been implicated in promoting several types of tumor

formation, such as liver and skin tumorigenesis and rhabdomyosarcoma.We found that YAP mRNA

was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2) when

compared to the androgen-sensitive LNCaP cells. YAP knockdown greatly reduced the migratory and

invasive rates of LNCaP-C4-2 cells. Importantly, ectopic expression of YAP was sufficient to promote

LNCaP cells from androgen-sensitive to androgen-insensitive in vitro and YAP conferred castration

resistance in vivo. Deletion of MST1/2 (core tumor suppressors in the Hippo pathway) or YAP did not

affect the prostate development. YAP activation or MST1/2 inactivation was not sufficient to promote

prostate tumorigenesis.

Biography: Dr.Dongobtained his Ph.D. at Zhejiang University, China.He went on to receive further training as a Postdoctoral

Fellow at the University of Texas Southwestern Medical Center at Dallas, and then at Johns Hopkins University,

Baltimore, USA. Currently he is an Associate Professor at the University of Nebraska Medical Center, Omaha,

USA.

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Dr S Krishnamurthy University/Organization: Kidwai Memorial Institute of Oncology Bangalore

Breast Cancer in India- Where do we stand and where do we go?

reatment of Breast cancer has undergone quite an improvisation in the last 20 years since the

introduction of molecular biology, immunohistochemistry and availability of targeted therapy.We

present our last 6 years’ experience in treating 862 Breast cancer patients in a single unit at a Regional

cancer centre in India. Total of 862 breast cancer patients have been treated at our institute in a

singlesurgical oncology unit from 2010 to 2016. Maximum incidence was observed in the age group 35-

64 years (710/82.4%) and least in above 65 years (73/ 8.5%) with almost an equal number of patients

coming from rural (51.9%) and urban (48.1%) population. Right sided breast cancer (56%) dominated

compared to left (43.4) whereas 0.6% were bilateral. A higher incidence was noted amongst

postmenopausal (54.2%) compared to premenopausal women (45.8%). Maximum patients were of

Luminal A category (35%) with most of them presenting as Stage II (42.5%) and III (44.4%) disease.

Triple Negative tumours contributed to significant 32.7% of the disease. 338 patients were given

neoadjuvant chemotherapy before surgical management. 21 patients underwent Breast conservation

surgery with Sentinel Lymph node biopsy done in 9 patients with 100% sentinel Lymph node

identification rate while the rest underwent modified radical mastectomy. Adjuvant chemotherapy and

Radiotherapy was administered to 437 and 702 patients respectively whereas 198 patients were given

targeted therapy. Hormonal therapy was offered to 460 patients based upon their receptor status.In a

developing country where health insurance cover and governmental policy is not available for the

patients, it remains a challenge to offer the advanced management to all patients attending a regional

cancer centre.

Biography: M.ch SURGICAL ONCOLOGY (AUGUST 1994); M.S.GENERAL SURGERY (FEBRUARY 1987); M.B.B.S (JULY

1982). Joined the institute as lecturer in 1987, promoted as assistant professor 1993, professor 2002 and heading

the department of surgical oncology since 2015. Teaching super specialty students (8) every year, published 40

articles in national/ international journals, participated in 8 global projects.

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Paola Bettinsoli Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy

Giulia Ferrari-Toninelli Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy

Sara Anna Bonini Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy

Michela Guarienti Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy

Davide Cangelosi Laboratory of Molecular Biology, GianninaGaslini Institute, Genova, Italy

Luigi Varesio Laboratory of Molecular Biology, GianninaGaslini Institute, Genova, Italy

Maurizio Memo Laboratory of Molecular Biology, GianninaGaslini Institute, Genova, Italy

Tropomodulins are new Favorable Prognostic Biomarkers in High-Risk Neuroblastoma

euroblastoma is a pediatric tumor of the sympaticoadrenal lineage of the neural crest

characterized by an extreme molecular and clinical heterogeneity, which is the main cause of the

unsatisfactory response to standard multimodal therapy. The identification of new and selective

biomarkers is crucial to fill the gaps about the biological and molecular mechanisms of neuroblastoma

and to improve cancer therapies. This study identified a positive and promising correlation between

Tropomodulins (Tmods) proteins and neuroblastoma. Tmods bind the pointed end of actin filaments,

regulate polymerization and depolymerization processes, modifying actin cytoskeleton dynamic and

influencing neuronal development processes. High expression levels of Tmods positively correlate with

high survival probability neuroblastoma patients’. Functional studies on neuroblastoma cell lines

demonstrated that Tmod 1 Knockin induced cell cycle arrest, cell proliferation arrest and a mature

functional differentiation. Tmod 1 overexpression is responsible of particular cell morphology and

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biochemical changes, which direct cells towards a neuronal prognostic favorable differentiation profile.

On the contrary, Tmod 1 downregulation caused the loss of mature cell differentiation for the

development of neuroendocrine cell characteristics, delineating an aggressive and prognostic

unfavorable tumor behavior. This work indicates that Tmods can be the innovative and prognostic

favorable biomarkers in high-risk neuroblastoma and contributes to understanding new biological

mechanisms to improve personalized therapeutics opportunities.

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Nina Mikirova Organization: Riordan Clinic

High-Dose Intravenous Vitamin C as Sole Therapy and in

Combination with Cytotoxic Chemotherapy in Patients with Cancer

itamin C has been shown to protect against oxidant injury at physiological concentrations and has

been suggested as having both a preventative and therapeutic role in a number of pathologies

when administered at pharmacological levels. In our clinic we treat cancer patients by high doses of

vitamin C intravenously (15-75 grams) during 40 years. According to our data,there was positive

response to IVC, which was demonstrated by measurements of inflammation (C- reactive protein)

andinflammatory/angiogenesis cytokines. 174 cytokines with tumor markers were determined in

cancer patients before and after a series of IVC treatments. The average levels (z-scores) for

inflammatory and angiogenesis promoting cytokines, that were higher than averages for healthy

controls, decreased over the course of treatment. A decrease in the level of inflammation correlated

with the decrease in the levels of tumor markers. Clinical studies of chemotherapy with vitamin

Cdemonstrated thatIVC does not interfere with anti-tumor effects of chemotherapy. IVC may improve

time to relapse, enhance reductions in tumor mass and improve survival in combination with

chemotherapy. IVC treatment improves quality of life, physical function, and toxicities associated with

chemotherapy. Our Phase I clinical study and other trials indicated that IVC can be administered

safely with relatively few adverse effects.

Biography: Nina Mikirova, PhD, Dr. Mikirova is the Director of research at the Riordan Clinic. After graduation from

Moscow State University in Russia, she worked atthe Institute of Bio-Medical Problems and joined the Riordan

Clinic in 1997. Her areas of research focus include: the effect of high dosage vitamin C on cancer, inflammation

and angiogenesis; energy metabolism of mitochondria in cancer cells; modulation ofthe levels of progenitor and

stem cells in circulation by nutraceuticals.

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Runsheng RUAN Organizations: Xiamen Key Laboratory for Translational Medicine in Cellular Theranostics of Cancer, Xiamen

University, People’s Republic of China

Clinical And Immunological Response to in Vivo Whole Cancer

Cell Antigen Priming Followed By Adoptive T-Cell Therapy in Terminal Cancers

trategies to enhance an antigen specific immunity against cancer have been met with limited

clinical success. We adopt a 2-tier protocol coupling active with passive immunization, allowing a

prospective clinical evaluation of survival in 31 terminal cancer patients. Treatment commences with

subcutaneous inoculation of whole cancer cell antigen followed by re-infusion of ex vivo expanded

autologous T cells. Tumour-specific cytotoxic T cells were confirmed via Elispot and Real-time Cell

Analyzing (RTCA) Assay, and serum cytokines werealso measured pre and post therapeutically.

Statistical tests show tumour-specific T cell response is effectively invoked post treatment. Spearman

correlation analysis determined significant association between higher post treatment cytotoxicity

scores and longer survival duration in months(R=0.59, p=0.005). This result is mirrored by the Elispot

count. Prospective controlled trials are needed to further clarify the role of cancer whole antigen

immunization with adoptive cell therapy, but these encouraging preliminary observations suggest that

this combination can induce more durable responses to immunotherapy.

Biography: Professor Ruan received his medical degree from Fujian Medical University and holds a MD degree from Zurich

University of Switzerland. He did his post-doctoral training at the Cancer Research Institute of Zurich University

Hospital. Professor Ruan is a multi-faceted personality. He is an ENT Head & Neck surgeon while at the same

time being deeply involved in applied cancer research. He currently is the Director of Xiamen Key Laboratory for

Translational Medicine in Cellular Theranostics of Cancer, and his research interests lie in the area of cellular

medicine for cancer immunotherapy.

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Shun Young Im

Mechanism of CK2 Activation and its Expression in Human Breast Cancer

he protein kinase CK2(formerly Casein Kinase II) is implicated in tumorigenesis and

transformation. However, the mechanisms of CK2 activation and the role of CK2 in breast

cancer remains to be elucidated.

Methods: CK2 activity, phosphorylation, and protein expression were determined in ER+ MCF-7 and

T47D, and ER- MDA-MB-231 human breast cancer cell lines. The expression of the various genes

involved in reactive oxygen species (ROS) metabolism and CK2 in human breast cancer tissues were

investigated using RT2 PCR array (Qiazen), and immunohistochemistry, respectively.

Results: Estrogen increased CK2 activity and phosphorylation in ER+, but not in ER- cell lines,

which were inhibited by the antioxidant N-acetyl-L-cysteine (NAC). H2O2 enhanced CK2 activity and

phosphorylation. Estrogen increased ROS generation in ER+, but not in ER- cell lines through

activation of p38 MAPK. The PCR array demonstrated that, among the 115 oxidative stress-related

genes examined, 11.3% genes were downregulated and 2.6% genes were upregulated in ER+/PR+, 7.0%

genes were downregulated in HER2+, and 6.1% genes were upregulated in triple negative breast

cancer tissues, respectively.Nuclear CK2 protein expression was observed in 100% (15/15), 100%

(15/15) and 92% (12/13) of ER+/PR+, HER2+, and triple negative cancer tissues, respectively.

Conclusios: The data suggest that 1) estrogen activated protein kinase CK2 via the induction of

ROS/p38 pathway 2) there were no significant differences in the expression of oxidative stress-related

gene and CK2a protein among the three different types of human breast cancer cells.

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David Vesely University of South Florida, Tampa

Cardiac Hormones for the Treatment of Cancer

our heart hormones, namely atrial natriuretic peptide (ANP), long-acting natriuretic peptide

(LANP), vessel dilator and kaliuretic peptide reduce up to 97% of cancer cells in vitro. These four

cardiac hormones eliminate up to 80 % of human pancreatic adenocarcinomas, 2/3rds of human breast

cancers and up to 89% of human small cell lung cancers growing in athymic mice. ANP intravenously

for 3 hours after “curative” lung surgery as an adjunct to surgery results in a two year relapse-free

survival of 91% compared to 75% with surgery alone. Their anticancer mechanisms of action involve

binding to receptors on the cancer cells followed by 95% inhibition of the conversion of inactive to active

rat sarcoma-bound guanosine triphosphate (RAS)-mitogen –activated protein kinase kinases 1/2 (MEK

1/2 ) (98% inhibition)-extracellular signal-related kinases 1/2 (ERK1/2 ) (96 % inhibition) in cascade

cancer cells. They are dual inhibitors of vascular endothelial growth factor (VEGF) and its VEGF2

receptor (up to 89% ) They also inhibit MAPK9 i.e. c-JUN-N-terminal kinase 2. One of the downstream

targets of VEGF is B-catenin, which they inhibit up to 88%. These four peptide hormones inhibit the

Wingless-related integration site (WNT) pathway 68% and WNT secreted-Frizzled protein is reduced

by up to 84%. Signal transducer and activator of transcription 3 (STAT 3), a final “switch” that

activates gene expression that leads to malignancy, is specifically decreased up to 88 % by these

peptides as they do not affect STAT 1. There is cross –talk between the RAS-MEK 1/2-ERK 1/2 kinase

cascade , VEGF, B-catenin, JNK, WNT, and STAT pathways and each of these pathways and their

cross talk is inhibited by these peptide hormones. They enter the nucleus of cancer cells where they

inhibit the proto-oncogenes c-Fos (up to 82 %) and c-Jun (up to 61%). Conclusion: These multiple

kinase inhibitors have both adjunct and primary anticancer effect ANP is one of four hormones

synthesized by the ANP prohormone gene.

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Doni Dermawan Padjadjaran University, Indonesia

The Combination of Zingiberis officinale var.rubrum and Piper retrofractum Based on Microencapsulation Technology

as an Anticancer Drug

ancer is a disease that causes high mortality rates in Indonesia and has a tendency to increase. A

wide variety of prevention and treatment of cancer has been done in Indonesia but there is no

treatment that is really effective. Indonesia has a huge potential in natural resources, including plants

that can be used as medicine. Piper retrofractum and Zingiberis officinale var. rubrum are plants

which has anticancer activity in the active ingredient. By using the method of literature study, this

paper focuses on assessing the activity and effectiveness of the combination of the active ingredient in

Piper retrofractum and Zingiberis officinale var. rubrum that have a potential synergistic effects as

anticancer in the appropriate dosage form. Curcumin can induces apoptosis of cancer cell and piperine

as an antioxidant that inhibits the free radical chain oxidative so it can prevent the oxidative stress.

Optimization of the extraction of active ingredients piperine from Piper retrofractum and curcumin

from Zingiberis officinale var. rubrum can be done by soxhlet extraction method with solvent ethanol

95%. Soxhlet method yields an efficient curcumin and piperine extraction, the efficiency of solvent and

time. The extract that obtained from the extraction process should be standardized to ensure its

quality so it implies safety and efficacy of dosage form produced. Effort to maximize the activity and

effectiveness as an anticancer, extract can be made dosage form based on microencapsulation

technology with variation concentration of core and coating agent using spray drying techniques. The

formulation technology of the combination of Piper retrofractum and Zingiberis officinale var. rubrum

based on microencapsulation is expected to provide a therapeutic effect that is secure, effective, and

efficient against cancer.

Keywords : Curcumin, Microencapsulation, Piperine, Piper retrofractum, Zingiberis officinale var.

rubrum

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Palma Giuseppe National CancerInstitute, IRCCS - ”G. Pascale” Foundation, Via Mariano Semmola, 80131, Naples, Italy

Mariconda Annaluisa Departmentof Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano (SA), Italy;

Rea Domenica National CancerInstitute, IRCCS - ”G. Pascale” Foundation, Via Mariano Semmola, 80131, Naples, Italy

Barbieri Antonio National CancerInstitute, IRCCS - ”G. Pascale” Foundation, Via Mariano Semmola, 80131, Naples, Italy

Domenico Iacopetta Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Arcavacata di Rende (CS), Italy

Maria Stefania Sinicropi Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Arcavacata di Rende (CS), Italy.

Longo Pasquale Departmentof Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano (SA), Italy;

Arra Claudio National CancerInstitute, IRCCS - ”G. Pascale” Foundation, Via Mariano Semmola, 80131, Naples, Italy

Saturnino Carmela Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano (SA), Italy.

New Topoisomerase Inihibitor for Breast and Pancreas Cancer

ecently, some authors reported that the Topoisomerase enzymes such as TOPO II is more

expressed in aggressive subset of tumors (for example breast tumor that overexpresses HER-

2/neu).Based on these evidences recently our group has synthesized a new molecule, called SC4, which

inhibits the TOPOII, reducing the proliferation and acts negatively on the cellular migration;

furthermore SC4 shown in vivo an antiproliferative effect and a reduction in the systemic toxic effects.

We have tested SC4 on two cancer cell lines, that representing the principal "Big Killer" of the

oncology: pancreatic cancer human cell (Mia-PaCa2) and triple negative breast cancer human cell

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(MDA.MB231). In vitro cytotoxic assays have demonstrated the ability of SC4 to inhibit cell

proliferation. The MTT assay , FACs Colony Assay results support the inhibition of proliferation.

Likewise, we performed two experimental in vivo to evaluate the SC4 inhibition activity on

proliferation and migration, and to assess the degree of safety.

Orthotopic cancer xenograft mouse models and in vivo models of secondary localization (Lung

Colonization)confirm the anticancer activity. In conclusion SC4 inhibits proliferation and migration of

human tumor cell lines by blocking the activity of TOPO II, and may be considered as a potent

inhibitor of tumor growth and invasion in mouse model; for these reasons could be considered a valid

prototype for the development of new antineoplastic therapies.

Biography He has worked as Fellow Researcher at the National Institute of Cancer - I.R.C.C.S. “G. Pascale Foundation”

since 2007. In the meantime he was Fellow Researcher at Institute of Endocrinology and Oncology “G. Salvatore”

- National ResearchCouncil, a national institute specialized in basic research on tumor biology.From 2002 to 2005

he was a junior clinical Fellow Researcher at San Raffaele Hospital, Cancer Immunotherapy and GeneTherapy

Dept., where he worked on the development of anti-cancer vaccines against melanoma based on dendritic

cellstransfected with lentiviral vector. His activity led to a clinical trial performed by MolmedSpA (Milan, Italy).

From 2005 to2007 he was in charge of the development of oncology murine models for testing new drug

candidates at CEINGE Scarl, abiotechnology consortium located in Naples, Italy.He is the author of 30 papers in

peer-reviewed international Journals.Giuseppe has a B.Sc, M.Sc in Medical Biotechnology (University of Naples

“Federico II”, Italy).

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Gregory Lee UBC Center for Reproductive Health, Vancouver, Canada

Distinct Functional Roles of Cancerous Immunoglobulins in

Cancer Immunology

he immune system in cancer cells was revealed with the understanding that immunoglobulins

expressed on the cancer surface play important roles in cancer immunology. RP215 monoclonal

antibody generated in 1987 against ovarian cancer cell extract was shown to react specifically with a

carbohydrate-associated epitope mainly found in the variable region of immunoglobulin heavy chains

and expressed on the surface of almost all of cancer cells (designated in general as CA215). Since then,

RP215 has become a unique probe to study mechanisms of action by which the cancer cells are affected

by these immunoglobulins. Generally speaking, RP215 and anti-human immunoglobulins are equally

effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer

cells and reducing the volume of the implanted tumor in nude mouse animal models. Interaction

studies were performed between isolate cancerous immunoglobulins and/or CA215 and human serum

proteins, most of which exhibit either anti-cancer or pro-cancer properties. Therefore, it is hypothesized

that cancerous immunoglobulins may function to interact with these human proteins for the

growth/proliferation as well as protections of cultured cancer cells in human circulations. RP215 may

be further developed as candidates of anti-cancer drugs to target most of cancer cells for

immunotherapy of human cancer.

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Hafiz Muhammad Asif, (Ph. D)

University College of Conventional Medicine, Faculty of Pharmacy & Alternative Medicine, The Islamia University of

Bahawalpur

Prevalence, Risk Factors and Disease Knowledge of Breast

Cancer in Pakistan

reast cancer is the most common cancer in females all over the world with approximately one

million new cases each year as well as one of second leading causes of death among females. In

Pakistan, the most frequently diagnosed cancer among females is also breast cancer. Breast cancer is

more common in Pakistani population as compared to the Western population. In Pakistan every year

at-least 90,000 women suffer from breast cancer. One in every nine Pakistani women suffers from

breast cancer which is one of the highest incidence rates in Asia. Recently, incidence of breast cancer is

21.5% among all and 45.9% among female patients, reported. Its incidence in Pakistan is 2.5 times

higher than that in neighboring countries like Iran and India. Key factors that play role in the

development of breast carcinoma are the genetics and environment, the reproductive experience, the

effect of endogenous and exogenous hormones in females, the change in immune status, host

vulnerability and the biologic determinants of breast carcinoma. The present study is aimed to provide

awareness about breast cancer as well as an updated knowledge about the prevalence, risk factors and

disease knowledge of breast cancer in Pakistan.

Keywords: Breast cancer, incidence, prevalence, risk factors, Pakistan

Biography I, Dr. Hafiz Muhammad Asif have completed my Ph.D. in the field of Eastern Medicine (Clinical Methods &

Therapeutics) from Hamdard University, Karachi, Pakistan. I have published more than 80 papers in National

and International journals. I have attended many national and international conferences and seminars and

presented oral and poster presentations. I am member of many national and international academic and learning

bodies. I am serving as Assistant Professor in University College of conventional medicine, Faculty of pharmacy

& alternative medicine, The Islamia University of Bahawalpur.

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Henry I.C. Lowe University/Organization: Bio-Tech Research & Development Institute

Tillandsia recurvata: A Natural Plant with Anti-Prostate Cancer Potential Targeting Kinases

rostate cancer is the second most common cause of death from cancer in men of all ages. The three

conventional treatment options include surgery, radiation and chemotherapy. In many cases, these

treatments are used in combination. Increased resistance to current chemotherapies by prostate cancer

calls for an urgent need to discover and develop new therapeutics that can slow the growth of cancer

cells while having lesser side effects on patients. In an effort to discover new anticancer drugs from

natural products, several Jamaicanplants were screened for anticancer activity. The Jamaican Ball

Moss (Tillandsia recurvata L.) was one such plant that exhibited potent activity against the prostate

cancer cell lines in vitro and in vivo. To explore the mechanism of action of the plant material, a crude

extract of Ball Moss was screened for interaction with over 450 kinases. The crude extract was active

against 5 kinases (kd = 8-14 μg/ml), of which 4 are implicated in prostate cancer onset and

proliferation. The kinases are; CSNK2A2, DRAK1, GAK and MEK5. Based on our scientific

determination of the molecular target for this potent extract, our lab produced a nutraceutical (Alpha

Prostate Formula) for the prevention and treatment of prostate cancer.

Biography Dr. Henry Lowe, , O.J., C.D., J.P., Ph.D., D.Sc. (Hons.), F.R.S.H, isin medicinal chemistry and has contributed

approximately 50 years in the fields of science and technology and the health sciences nationally, regionally and

internationally.He has earned several recognitions nationally and regionally, including the Order of Jamaica and

Commander of the Order of Distinction. He is an Adjunct Professor in the Department of Medicine, University of

Maryland School of Medicine, USA and Distinguished Adjunct Professor of Ethno-medicinal Chemistry,

University of Technology, Jamaica. He is a public servant, author, educator and successful entrepreneur.

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Laili Rahayuwati Faculty of Nursing, Universitas Padjadjaran

Witdiawati Faculty of Nursing, Universitas Padjadjaran

Erna Irawan Faculty of Nursing, Universitas Padjadjaran

Nutrition Therapy For Breast Cancer During Chemotherapy A

Qualitative Study onthe Needs of Breast Cancer Patients

he high prevalence and incidence of breast cancer in Indonesia remains a disheartening issue, for it

has turned out to be a threat for the quality of Indonesian women’s life. Let alone the fact that the

patients and their families often lose interest in recognizing the issue of breast cancer, both benign and

malignant. Besides, the problem faced by breast cancer patients in determining which kind of

diagnosis or best therapy is still overlooked by the patients as well as their family members. This

includes their indifference toward the patients’ nutrition during chemotherapy, which now thus must

be taken into consideration.

This research aims at observing therapy needs in general, particularly that of nutrition of

breast cancer patients during their chemotherapy and post-therapy period. This research is the result

of qualitative data collected by case study on 17 breast cancer patients undergoing chemotherapy in Al-

Ihsan Hospital, Bandung District and HasanSadikin Hospital, Bandung City. These patients have

undergone an in-depth interview either on their own or accompanied by a family member.

The result of the qualitative research is obtained through content analysis observation, showing

a shallow understanding about therapy, both generally and specifically, regarding the importance of

nutrition and the escalation of its amount on the patient and their families. In fact, one of the things

that support the patient’s immune system during their chemotherapy is the sufficient condition of

nutrition. Not only that, the result shows that cancer survivors claim they keep a balanced intake of

nutrition during and after therapy. Therefore, it is necessary to make a formula about nutrition needs

of breast cancer patients, in the preparatory, momentary, and preempting stage of chemotherapy.

Keywords: nutrition therapy, breast cancer.

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Menna Fouda MSc., Institute: Tanta University Hospitals , Faculty Of Medicine ,Clinical Oncology &Nuclear Medicine department, Egypt

Fawzy Z. Sherif MD Institute: Tanta University Hospitals , Faculty Of Medicine ,Clinical Oncology &Nuclear Medicine department, Egypt

Amr A.Ghannam MD Institute: Tanta University Hospitals , Faculty Of Medicine ,Clinical Oncology &Nuclear Medicine department, Egypt

Safinaz H. Al-shorbagy MD Institute: Tanta University Hospitals , Faculty Of Medicine ,Clinical Oncology &Nuclear Medicine department, Egypt

Menna Fouda ( Assistant Lecturer of Clinical Oncology& Nuclear Medicine) Institute: Tanta University Hospitals ,

Faculty Of Medicine ,Clinical Oncology &Nuclear Medicine department, Egypt

Prognostic Value of Breast Cancer Subtypes Based on ER/PR,

Her2 Expression and ki-67 Index in Women Received Adjuvant Therapy after Conservative Surgery for Early Stages Breast

Cancer reast cancer is the most common malignancy in women, accounting for 29% of all female cancers. it

accounts for < 1% of all cancer cases in men. In a population based cancer registries in Gharbia,

Egypt, breast cancer was the most frequent cancer among Egyptian females. Prognostic information for

the individual patient is based on the analysis of biological markers in the primary tumour including

(ER), (PR), (HER2) and Ki67, together with age, tumour size, histological grade and lymph node

involvment. Molecular subtyping of breast cancer may provide additional prognostic information

regarding patient outcome.

Objectives: To evaluate the prognostic effect of breast cancer subtypes on local relapse rates, distant

metastases, and survival in women underwent breast conservative surgery for early stages breast

cancer.

Material and Methods:Data of 100 patients affected by early stage breast cancer and treated with

breast-conserving therapy were reviewed. Patients were grouped, based on the basis of receptor status

and HER-2 status, patients were grouped, as: luminal A (ER + and/or PR+, Ki67 low and HER2-),

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luminal B (ER + and/or PR+, Ki67 high and/or HER2+), HER2-positive (ER-, PR- and HER2+) and

triple negative (ER-, PR, HER2-). Distribution of variables among subtypes was evaluated with

Pearson’s test. Survival rates were calculated with life tables; Cox regression stepwise method was

used to identify predictive variables of survival.

Results:Median age was (range 18-50) and median follow up time of 40 months (range 36.83-

43.17).Breast cancer specific survival and distant metastases rates were different among breast cancer

subtypes (both outcomes P= 0.001) , there was significant difference regarding local relapse rates (P=

0.002 ). Axillary nodes status (P= 0.007), adjuvant therapy (P= <0.001) and breast cancer subtypes

resulted prognostic factors of breast cancer specific survival; axillary node status (P= 0.007) and breast

cancer subtypes had an impact on distant metastases.

Conclusions: In our study, breast cancer subtype seems a prognostic factor of breast cancer specific

survival and distant metastases rates & of local relapse rate. Patients could be submitted to

conservative surgery, if feasible, but considering the differences in survivals, patients with worse

prognosis should receive more aggressive adjuvant treatment.

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Mostafa I. Waly University/Organization: Department of Food Science and Nutrition, College of Agricultural and Marine Sciences,

Sultan Qaboos University, Muscat, Oman

Functional Foods in the Primary Prevention of Colon Cancer

ncreased consumption of refined carbohydrates, sugars, and saturated fats is accompanied by low

intake of fruits and vegetables; this dietary pattern is involved in the etiology of different types of

cancers, the global cause of morbidity and mortality in the Western countries and gulf region.

Colorectal cancer, CRC, is among the primary preventive cancers if adequate intake of antioxidants

was provided either by diet, and nutritional supplements. Our research group at Sultan Qaboos

University has successfully identified phytonutrients- rich dietary bioactive agents (Date Pit

Pomegranate Peel, Mushroom Extract, and Nabag Extract) which provide antioxidant protective effect

against oxidative stress-induced CRC, using in-vivo experimental study models. Our results have

shown a net subjective improvement in the CRC pathogenesis as evident by a marked decrease in

tumor growth, increase in intra cellular glutathione level, and antioxidant enzymes-improved

activities. It was concluded that the high intake of plant-based foods might be adopted as a dietary-

based intervention approach for the primary prevention of oxidative-stress mediated cancers, including

CRC. The mechanism was thought to be by abrogating oxidative stress in carcinogenic cells.

Biography: Dr. Mostafa Waly obtained his PhD in 2003 in Nutritional Biochemistry from the Department of Biomedical

Sciences at Northeastern University, Boston, USA. He is currently holding the position of associate professor,

Food Science and Nutrition department, Sultan Qaboos University in Oman. Dr. Waly has received several

academic awards and he is an active member in international advisory board of American Society of Nutrition

and Experimental Biology of Medicine Society. Dr. Waly is the author of many scientific publications recognized

by local and international bodies. His research interests have been in the role of dietary antioxidants and B

vitamins in the primary prevention of chronic diseases. Dr. Waly performed several consultancies for UNICEF

and WHO.

I

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Muna Fathy

Association Between Environmental Tobacco Smoke Exposure

and Lung Cancer Susceptibility: Modification by Antioxidant Enzyme Genetic Polymorphisms

nvironmental tobacco smoke (ETS) is the primary etiologic factor responsible for lung cancer.

However, only 10–15 % of smokers develop lung cancer, suggesting a genetic role in modifying

individual susceptibility to lung cancer. Antioxidant enzymes and genetic polymorphisms should be

considered.

Aim: The present study aimed to evaluate the role of antioxidant enzyme activity and genetic

polymorphisms in modifying the susceptibility to lung cancer among individuals exposed to ETS.

Subjects and Methods: A total of 150 male subjects were divided into three groups: 50 lung cancer

patients, 50 chronic smokers, and 50 passive smokers. Genotyping of microsomal epoxide hydrolase

(mEH) exon 3 (Tyr113Hist) and exon 4 (Hist139Arg) polymorphisms were done by the polymerase

chain reaction-restriction fragment length polymorphism technique. MnSOD (Val16Ala) polymorphism

was detected by the real time-TaqMan assay. Erythrocyte MnSOD activity was measured

spectrophotometrically.

Results: ETS-exposed individuals (both active and passive smokers) who carried the His allele of

mEH exon3 have a 2.9-fold increased risk of lung cancer (odds ratio [OR] 2.9, P < 0.001). In addition,

ETS-exposed carriers of the Arg allele of mEH exon 4 have a 2.1-fold increased risk of lung cancer (OR

2.1, P = 0.024). However, no association between the MnSOD Val16Ala polymorphism and lung cancer

was detected among ETS-exposed individuals (OR 1.6, P = 0.147), although the lung cancer group had

significantly lower MnSOD activity than the chronic or passive smoker groups (P = 0.03). Conclusions

Exons 3 and 4 polymorphisms of the mEH gene may contribute to lung cancer susceptibility through

disturbed antioxidant balance. However, this was not thecase with the MnSOD Val16Ala single-

nucleotid polymorphism. Antioxidant enzymes may modulate the influence of ETS exposure on lung

cancer risk.

E

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Srabović N Department of Biochemistry, Faculty of Pharmacy, University of Tuzla, Tuzla , Bosnia and Herzegovina

Softić A Department of Biochemistry, Faculty of Pharmacy, University of Tuzla, Tuzla , Bosnia and Herzegovina

Smajlović A Department of Biochemistry, Faculty of Pharmacy, University of Tuzla, Tuzla , Bosnia and Herzegovina

Mujagić Z Department of Biochemistry, Faculty of Pharmacy, University of Tuzla, Tuzla , Bosnia and Herzegovina

VEGF and IL-6 Profile in Patients with Invasive Breast Cancer

he aim of this study was to investigate VEGF expression in tumour tissue in patients with breast

cancer in relation to stromal tissue and normal breast tissue in patients with benign breast

disease, and in relation to circulating VEGF and IL-6 levels, preoperatively and postoperatively.

Samples from 20 patients with breast cancer and 15 patients with benign breast disease were included.

Immunohistochemical staining was used for determining VEGF expression in tissue samples.

Measuring VEGF and IL-6 levels was conducted by ELISA.

Differences in VEGF expression between tumour and stroma were significant (p=0,007) and

between tumour and normal breast tissue in benign disease patients (p=0,0001), and also between

stromal and normal breast tissue (p=0,004). Circulating VEGF were significantly higher in serum from

patients with breast cancer than in patients with benign breast disease pre- and post-operatively

(p=0,023; p=0,019). VEGF levels were higher postoperatively in serum (p=0,009) and in seroma

(p=0,0001). Circulating IL-6 were significantly higher in serum from patients with breast cancer than

in patients with benign breast disease (p=0,023) postoperatively. IL-6 levels were higher

postoperatively in serum (p=0,015) and seroma (p=0,0001). IL-6 levels were significantly higher in

serum from patients with benign breast disease postoperatively (p=0,018). Statistically significant

correlation between VEGF and IL-6 in seroma from patients with breast cancer was found (p=0,009).

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Results from present study suggest sinergistic activity of VEGF and IL-6 in wound healing process

after breast cancer surgery.

Biography Nahida Srabovic is assistant professor at The Department of Biochemistry, Faculty of Pharmacy, University of

Tuzla, Tuzla, Bosnia and Herzegovina.

Nahida Srabovic was born in Tuzla, Bosnia and Herzegovina on 11 January 1982. She graduated from High

School in Lukavac and from the University of Tuzla, Faculty of Science with a Bachelor of Chemistry in February

2005. She completed her Master of Science degree in Biochemistry in April 2010 at University of Sarajevo,

Sarajevo, Bosnia and Herzegovina. After receiving her education she remained at the Department of

Biochemistry, University of Tuzla as teaching assistant and researcher. She completed her PhD thesis in October

2012 at University of Tuzla.

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Rajeswari Narayanappa University/Organization: Department of Biotechnology, CD Sagar Center for Life Sciences, Dayanandasagar College

for Engineering, Kumarswamy Layout, Bangalore 560 078. India

Madhuri Aithal University/Organization: Department of Biotechnology, CD Sagar Center for Life Sciences, Dayanandasagar College

for Engineering, Kumarswamy Layout, Bangalore 560 078. India

DNA methylation Analysis of genes in Notch signalling

pathway in human glioblastoma FFPE tissues

ene expression can be disrupted either through genetic or epigenetic alterations. In cancer, over

half of tumor suppressor genes are affected through methylation. It can also affect other important

signal transduction pathways leading to altered receptor function, altered function of transcription

factors, and disruption of normal cell–cell interaction. Aberrant methylation can occur at very early

stage in cancer leading to malignancy, hypermethylated gene promoters hold great promise as tumor

markers for early detection and their reversible nature provides an effective drug target for gene

reactivation.

The Notch signaling pathway is one such developmental pathway governing cell fate decisions,

differentiation, cell proliferation and apoptosis. Deregulated Notch signaling is found to have a

prominent role in development of various cancers. Glioblastoma is most common primary brain tumor

with very poor prognosis despite aggressive treatment regiments. Therefore it is important to study

genetic and epigenetic events leading to gliomagenesis and consequent aggressive phenotype to guide

new treatment strategies.

The aim of this study was to detect Notch pathway genes potentially regulated by promoter

methylation from human glioblastoma FFPE sections. Using methylation specific PCR, we identified

Notch3 and JAG2 promoters as hypermethylated and Notch4 with both methylated and unmethylated

promoter. Despite methylation, Notch3 showed robust gene expression suggesting its partial

dependency on promoter methylation and presence of alternative regulatory mechanisms. However,

low gene expression of JAG2 and absence of Notch4 gene expression suggest possibility of epigenetic

silencing. This study provides gene expression and DNA methylation profiles of Notch pathway genes

in glioblastoma. Epigenetic mechanisms can be used as markers that may guide treatment decisions.

G

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Farrukh Aqil Department of Medicine and Toxicology, University of Louisville,

James Graham Brown Cancer Center and Toxicology, University of Louisville, Louisville, KY 40202, USA

Radha Munagala Department of Medicine and Toxicology, University of Louisville,


Hina Kausar James Graham Brown Cancer Center and Toxicology, University of Louisville, Louisville, KY 40202, USA

Ashish Agrawal James Graham Brown Cancer Center and Toxicology, University of Louisville, Louisville, KY 40202, USA Jeyaprakash Jeyabalan James Graham Brown Cancer Center and Toxicology, University of Louisville, Louisville, KY 40202, USA

Al-Hassan Kyakulaga Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA

Ramesh Gupta Department of Medicine and Toxicology,


Exosomal Formulation Enhances Therapeutic Response of Celastrol Against Lung Cancer

elastrol (CEL), a plant-derived triterpenoid, is a known inhibitor of Hsp90 and NF-κB activation

pathways and has recently been suggested to be of therapeutic importance in various cancers.

However, the molecular mechanisms of celastrol- mediated effects in lung cancer are not systematically

studied. Moreover, it suffers from poor bioavailability and offsite toxicity issues. This study aims to

study the effect of celastrol loaded into exosomes against two non-small cell-lung carcinoma (NSCLC)

cell lines and explore the molecular mechanisms to determine the proteins governing the cellular

responses. We observed that celastrol inhibited the proliferation of A549 and H1299 NSCLC cells in a

time- and concentration- dependent manner as indexed by MTT assay. Mechanistically, CEL pre-

C

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treatment of H1299 cells completely abrogated TNFα-induced NF-κB activation and upregulated the

expression of ER-stress chaperones Grp 94, Grp78, and pPERK. These changes in ER-stress mediators

were paralleled by an increase in apoptotic response as evidenced by higher annexin-V/PI positive cells

evaluated by FACS and immunoblotting which showed upregulation of the ER stress specific pro-

apoptotic transcription factor, GADD153/CHOP and alteration of Bax/Bcl2 levels. Exosomes loaded

with CEL exhibited enhanced the anti-tumor efficacy compared to free CEL against lung cancer cell

xenograft. CEL did not exhibit any gross or systemic toxicity in wild-type C57BL6 mice as determined

by hematological and liver and kidney function test. Together, our data demonstrate the

chemotherapeutic potential of celastrol in lung cancer and that exosomal formulation enhances its

efficacy and reduces dose related toxicity..

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Dr. Rania Zayed Professor of Clinical and Chemical Pathology, Cairo University

Regulatory T Cells; Key Role Players in Hematological

Malignancies

egulatory T cells (Tregs) are a specialized subpopulation of CD4+ T cells, which act to suppress the

activation of other immune cells. Tregs are either naturally occurring or induced.Tregs have

crucial role in induction of immune tolerance during infection, pregnancy, transplantation,

autoimmunity and neoplasias.They are recently recognized as key component of the tumor

microenvironment and important determinant of tumor progression; Tregsare implicated in both solid

tumor and hematological malignancies. Thus manipulation of Tregs represents an emerging

therapeutic approach to cancer treatment.

The following items will be discussed:

T regulatory Cells Types and function

Tregs induction mechanisms

Identification of Tregs

Mechanisms underlying the role of Tregs in hematological malignancies

Manipulation of Tregs as a targeted therapy in hematological malignancies

Biography: Rania Zayed is professor of Clinical and Chemical Pathology (Subspecialty: Hematology), Faculty of Medicine,

Cairo University, Egypt. She practices and teaches at Kasr Al-Ainy Hospitals and School of Medicine, Cairo,

Egypt. She had completed the doctorate degree in 2004. She earned certificates in medical education, research

methodology, research ethics, scientific writing and communication skills. Research interests include stem cells

and hepatitis C virus infection. Professor Rania shared in several national and international conferences in

hematology and stem cell research.

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Sadia Salahuddin Cornell University, Ithaca New York 14853. U.S.A, Lineberger Comprehensive Cancer Center, The University of

North Carolina, Chapel Hill USA, National University of Sciences and Technology, Islamabad 46000 ,Pakistan.

Joharia Azhar National University of Sciences and Technology, Islamabad 46000 ,Pakistan

Christopher B. Whitehurst Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill USA

Ishtiaq Qadri King Abdul Aziz University, PO Box 80216, Jeddah 21589, Saudi Arabia

Julia Shackelford Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill USA

Joseph S. Pagano Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill USA

Kristy L. Richards Cornell University, Ithaca New York 14853. U.S.A

Prevalence of Epstein–Barr Virus Genotypes in Pakistani Lymphoma Patients

he Epstein-Barr virus (EBV) is a herpesvirus infecting more than 90% of the human population.

The tropism of EBV for B lymphocytes is evidenced in its association with many

lymphoproliferative disorders. Different types of EBV (EBV-1 and EBV-2), classified on the basis of

EBNA-2 genotyping, have been reported in benign and malignant pathologies, but there is almost no

information about their frequency in the Pakistani population. The aim of this study was to determine

the frequency and distribution of EBNA-2-based EBV genotypes in lymphoma patients. Genomic DNA

was extracted from formalin-fixed paraffin embedded (FFPE) tissue samples obtained from 73 EBV-

DNA-positive lymphoma patients. The β-globin gene was amplified to assess the presence and quality

of cellular DNA from all samples. EBER-1 DNA was detected by PCR to confirm EBV presence in

tissue samples. EBNA-1 mRNA relative quantification by quantitative PCR substantiated EBNA-1

T

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mRNA overexpression in 52% of EBV-positive cases in comparison to an EBV-positive cell line control.

EBNA-2 genotyping was done by nested polymerase chain reaction (PCR). Among typable samples,

EBV-1 was present in 90.7%; EBV-2, in 9.3%. These results show that EBV-1 is the most prevalent

type in the lymphoma population of Pakistan, similar to reports from other countries. This definition of

EBV epidemiology in Pakistani lymphoma patients represents an important first step in using EBV for

prognosis and monitoring treatment response in patients.

Keywords: Epstein - Barr virus; Genotyping; Non-Hodgkin Lymphoma; Hodgkin Lymphoma; EBER-1;

EBNA-1;EBNA-2.

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Yasser Hussein Eissa Mohammed Department of Chemistry, Yuvaraja’sCollege, University of Mysore, Mysore- 570005 Karnataka, India.

Prabhakar B.T Molecular Onco-medicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri

Science College (A), Kuvempu University, Shivamogga- 577203, Karnataka, India.

Shaukath Ara Khanum Department of Chemistry, Yuvaraja’sCollege, University of Mysore, Mysore- 570005 Karnataka, India.

Design, Synthesis and Evaluation of Novel Pyridazine Pharmacophores on Migration and Invasion, A Major Event of

Cancer Metastasis

eoplastic metastasis is a major route where tumour cells transfer from the primary tumourand

colonize at other parts of our body to form secondary tumour. Cancer incidences are rising and

novel anti-neoplastic compounds with new mechanism of actions are essential for preventing cancer

related death. In the current examination, a novel series of pyridazine analogues 6a-m was synthesized

and evaluated against metastatic neoplastic cells. Experimental data postulated that compound 6j has

potential cytotoxic efficacy with prolonged activity against various cancer cells, including A549, HepG2,

A498, CaSki and SiHa cells. Moreover, compound 6j arrests the A549 migration and invasions

markedly by counteracting matrix metalloproteinase (MMP)-2 and MMP-9 expressions. Altogether, we

concluded that compound 6j down regulates MMP-2 and MMP-9, thereby impairs metastatic cancer

cell migration and invasions which can be translated into a potent anti-neoplastic agent.

Key words: Pyridazine; Metastasis; Migration and invasion; MMPs; Cancer.

N

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Zeev Blumenfeld Reproductive Endocrinology, OB/GYN, Rambam Health Care Campus, Technion-Faculty of Medicine, and

MEUHEDETH Med Services, Haifa, Israel.

An Ounce of Prevention is Worth a Pound of Cure"-Gnrh-

Acotreatment Significantly Preserves Fertility and Increases Pregnancy Rate in Addition to Cyclic Ovarian Function.

he late effects of cancer treatment have gained a worldwide interest among hematologists,

reproductive endocrinologists, oncologists, and all health care providers, and the protection against

iatrogenic infertility caused by chemotherapy assumes a high priority.

Methods:Recent metaanalysesof RCT'sconcluded that GnRHa cotreatmentalong chemotherapy

significantly decreasedPOF rate.However, cyclic ovarian function is not equivalent to fertility

[pregnancies].Therefore we evaluated thePR after exposure to gonadotoxic chemotherapy+ GnRHa vs

controls.We have administered a monthly depot IM injection of GnRH-agonistic analogue to 300 young

women exposed to gonadotoxic chemotherapy for malignant or non-malignant diseases, after informed

consent, starting before chemotherapy for up to six months, in parallel to, and until the end of

chemotherapy. These patients were compared to a control group of 200 patients of comparable age (14-

40 years), who were similarly treated [chemotherapy without GnRH-a]. Neither the age, nor the

diagnoses, or radiotherapy exposure differed between the two groups. The cumulative doses of each

chemotherapeutic agent and the mean or median radiotherapy exposure did not differ between the

groups. The patients who have not visited our clinic in the last 6 months were interviewed by phone to

verify the data on pregnancies. The study was approved by the institutional RB ethics [Helsinki]

committee.

Results: Less than 13% developed irreversible hypergonadotropic amenorrhea in the GnRHa

cotreatment group, vs 50% in controls [P<0.001]. The remaining patients resumed cyclic ovarian

function, and 90 patients spontaneously conceived 178 times, and were delivered of 129 healthy

neonates, in the GnRHa+chemotherapy group. In the control group only 55 pregnancies were reported

in 31 patients [P=0.02]. The age of the patients who spontaneously conceived, in the GnRHa group was

14-38 at chemotherapy compared to 14-30 y's in the control group. One patient, in the GnRHa group,

spontaneously conceived three times and was delivered of three healthy neonates despite two stem cell

transplantations [SCT], 11 years apart. Several patients spontaneously conceived up to six times.

GnRH-a cotreatment was beneficial not only against regular chemotherapy but also for lymphoma

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patients undergoing SCT in significantly decreasing the POF rate. The possible de-novo formation of

follicles by the surviving germline stem-cells brings about a decrease in FSH concentration and return

of regular cycles, ovulation, and even gestations. Most relevant to this equivocal and highly debatable

issue, is a publication from one of theprevious opponents to GnRH-a use for fertility

preservation,reporting that the use of GnRH-a during chemotherapy has significantly increased the

probability to conceive [OR= 12.87; P[0.001=. Furthermore, in keeping with our experience, two recent

prospective RCT [NEJM, 2015 and JAMA 2016] have found significantly higher pregnancy rate and

delivery rate, in addition to significantlyhigher cyclic ovarian function in the GnRHa+chemotherapy

group. In addition, they reported either similar orsignificantly higher survival rates of breast cancer

patients in the GnRHa+chemotherapy group vs. controls. Two recent expert committees have

concluded that GnRHa cotreatment in parallel to chemotherapy is beneficial in minimizing POF rate

and increasing pregnancy rate in survivors and recommended its use.

Conclusions: GnRHa cotreatment in parallel to chemotherapy is beneficial in minimizing POF rate

and increasing pregnancy rate in survivors. Therefore, it should be offered to every young woman

before gonadotoxic chemotherapy in addition to cryopreservation of embryos, ova, and ovarian tissue.

Future endeavors may include Sphingosine-1-Phosphate as a novel means for fertility preservation,

immunotherapy instead of chemotherapy, and in-vitro maturation [IVM] of primordial follicles from

the cryopreserved ovarian tissues to mature metaphase-II fertilizable oocytes for IVF. This may

completely omit the risk of reintroducing malignant cells while auto transplanting cryopreserved

ovarian tissue.

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Chanakya Nath Kundu Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Odisha,

751024, India

Quinacrine Induces Apoptosis in Cancer Cells by Forming a Functional Bridge Between TRAIL-DR5 Complex and

Modulating the Mitochondrial Intrinsic Cascade

eath Receptor 5 (DR5) is known to be an important anti-cancer drug target. TRAIL is a natural

ligand of DR5, but its drug action is limited because of several factors. A few agonistic ligands

were identified as TRAIL-DR5 axis modulators, which enhance the cellular apoptosis. Literature

suggest that quinacrine (QC) acts as a DR5 agonistic ligand. However, the detailed mechanism

explaining how QC interacts with TRAIL-DR5 axis has not been established. Also focused in vitro and

in vivo experimental analysis to validate the hypothesis is not yet performed. In this work, extensive

studies have been carried out using in silico analysis (molecular dynamics), in vitro analysis (cell based

assays) and in vivo analysis (based on mice xenograft model), to delineate the mechanism of QC action

in modulating the TRAIL-DR5 signalling. The MD simulations helped in identifying the important

residues contributing to the formation of a QC-TRAIL-DR5 complex, which provide extra stability to it,

consequently leading to the enhanced cellular apoptosis. QC caused a dose dependent increase of DR5

expression in cancer cells but not in normal breast epithelial cells, MCF-10A. QC showed a synergistic

effect with TRAIL in causing cancer cell apoptosis. In DR5-KD MCF-10A-Tr (DR5 knocked down) cells,

TRAIL+ QC failed to significantly increase the apoptosis but over expression of full length DR5 in DR5-

silence cells induced apoptosis, further supporting DR5 as a drug target for QC. An increase in the

release of reactive species (ROS and RNS) and activation of enzymes (FADD, CASPASES 3, 8, 9 and

cytochrome-C) indicated the involvement of mitochondrial intrinsic pathway in TRAIL+QC mediated

apoptosis. In vivo study pointed out that TRAIL+QC co-administration increases the expression of

DR5 and reduce the tumor size in xenograft mice. This combined in silico, in vitro and in vivo analysis

revealed that QC enhances the cellular apoptosis via the modulation of TRAIL-DR5 complexation and

the mitochondrial intrinsic pathway.

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Biography Chanakya N Kundu, Associate professor at School of Biotechnology, KIIT University, Bhubaneswar, completed

his PhD in Biochemistry from the Indian Institute of Chemical Biology, Kolkata Jadavpur, India. He later joined

Texas A&M University, Texas, USA as a postdoctoral research fellow. He worked three and half years on

mammalian molecular signal transduction pathways. Afterwards he worked at the University of Florida Shands

Cancer Center, Gainesville, USA, for two years on DNA damage and repair pathways in special reference to

cancer biology. In prior to join at KIIT University as an assistant professor he worked for one year at Cleveland

Clinic Foundation, Cleveland, Ohio, on translational research in colorectal cancer and WNT-β CATENIN

signaling. Currently the focus of his research work is to understand the molecular mechanism of metastasis,

angiogenesis in cancer stem cell signaling. He is trying to develop new chemotherapeutic cocktail which will not

only inhibits the bulk of cancer cells but also inhibit the cancer stem cell proliferation, angiogenesis as well as

reduce the inflammation in cancer patients. He has already published more than 50 peer reviewed research

articles in international journal, file two patent, written multiple book chapter, etc. He is the recipient of several

award such as young biomedical scientist of India, DBT-CREST,etc by the govt of India.

session introduction · go? reatment of breast cancer has undergone quite an improvisation in the...

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